This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Ambient air pollution is a major risk factor for cardiovascular morbidity and mortality. Short-term elevation in ambient particulate matter (PM) has been implicated in the pathogenesis of acute cardiovascular events including myocardial infarction, ventricular arrhythmias and ischemic stroke. A positive association has been identified between short-term increases in respirable or fine particles (particulate matter with aerodynamic diameter d10 [unreadable]m (PM10) or d2.5 [unreadable]m (PM2.5), respectively) and risk of hospitalization for congestive heart failure. The ultrafine PM is capable of directly entering systemic circulation through alveolar endothelium without having to go through phagocytosis of alveolar macrophages. These air contaminants may trigger a cascade of detrimental health effects involving cardiovascular and other systems through their pro-inflammatory effects. However, the precise mechanism of action behind long-term PM exposure-induced ischemic heart disease is essentially unknown. Ample evidence has implicated the essential role of endoplasmic reticulum (ER) stress in a number of environment-related disease conditions including obesity and insulin resistance. ER stress may directly induce compromised insulin signaling and cell survival although little information is available for the contribution from ultrafine PM air pollution. The central hypothesis of this proposal is that ultrafine PM directly triggers ER stress, compromised insulin signaling and impaired cardiac contractile function. We will employ state-of-the-art physiological and molecular biology techniques to evaluate the impact of ultrafine PM on ER stress, insulin signaling, intracellular Ca2+ homeostasis, and myocardial and cardiomyocyte contractile function, with or without intervention of ER stress inhibitors. Our long-term goal is to delineate the role of ER stress in the interplay between ambient particulate matter air pollution and cardiac dysfunction. Completion of this project should provide a therapeutic rationale for ER stress intervention for air pollution-associated heart problems.